Mucus production stimulated by IFN-AhR signaling triggers hypoxia of COVID-19, Liu et al. 2020

[jnmaciuch]

Mucus production stimulated by IFN-AhR signaling triggers hypoxia of COVID-19 (2020)​

Yuying Liu, Jiadi Lv, Jiangning Liu, Man Li, Jing Xie, Qi Lv, Wei Deng, Nannan Zhou, Yabo Zhou, Jiangping Song, Peng Wang, Chuan Qin, Wei-Min Tong & Bo Huang

Abstract

Silent hypoxia has emerged as a unique feature of coronavirus disease 2019 (COVID-19). In this study, we show that mucins are accumulated in the bronchoalveolar lavage fluid (BALF) of COVID-19 patients and are upregulated in the lungs of severe respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected mice and macaques. We find that induction of either interferon (IFN)-β or IFN-γ upon SARS-CoV-2 infection results in activation of aryl hydrocarbon receptor (AhR) signaling through an IDO-Kyn-dependent pathway, leading to transcriptional upregulation of the expression of mucins, both the secreted and membrane-bound, in alveolar epithelial cells. Consequently, accumulated alveolar mucus affects the blood-gas barrier, thus inducing hypoxia and diminishing lung capacity, which can be reversed by blocking AhR activity. These findings potentially explain the silent hypoxia formation in COVID-19 patients, and suggest a possible intervention strategy by targeting the AhR pathway.

Link (open access)

 

[jnmaciuch]

Given the discussion on this thread about runny nose during PEM, I thought it would be interesting to look into what signaling causes the creation of mucus/phlegm in normal viral infection.

Interferons have been of interest to me lately so I was wondering about their possible role here, especially given other findings in the field about the importance of epithelial-cell-specific interferons in resisting respiratory infection.

This study shows that exposure to interferon in the absence of any viral trigger is able to trigger the production of mucins, which makes it an interesting finding with respect to direct causality.

As always, obligatory acknowledgement that a finding like this doesn't necessarily mean that interferons themselves are "causative" of a specific PEM symptom, since it's possible for them to be induced downstream of something else [edit: or other signaling pathways might end up at the same place].

 

[jnmaciuch]

Explain like I'm brain-foggy:

As expected, this study first confirms that lung epithelial cells from SARS-CoV-2 patients (collected from bronchoalveolar lavages, basically fluid collected from a "wash out" of the lungs) generate mucus as part of the anti-viral response.

Interestingly, directly infecting lung cells with SARS-CoV-2 did not induce mucus (within 24 hrs). Based on findings of upregulated interferon (part of the first line of anti-viral defense of non-immune cells) in a humanized mouse model and in the human samples, the authors hypothesized that interferon itself was responsible for the mucus production.

Exposing the lung cells to both interferon beta and gamma induced expression of mucins within 24 hours. (Here it should be noted that SARS-CoV-2 is well known to downregulate the initial host interferon response as part of its immune evasion mechanism, which explains why it might have been detected in samples of patients that had been sick for days and had time to ramp up a counter interferon response, but not by directly infecting cells).

Further investigation using knockout cell lines and inhibitory drugs confirmed that mucins are induced by interferon signaling via the IDO-AhR pathway (IDO is an enzyme in the tryptophan-kynurenine pathway and AhR is a transcription factor).

Finally, the authors speculated that the action of interferon in the lungs may cause reduced lung capacity and hypoxia in infected mice. Exposing the lungs of mice to interferon beta or gamma induced the lung impairment phenotype, which was rescued by blockade of AhR signaling pathways.

 

[jnmaciuch]

One thing I'll note is that they didn't specifically confirm whether it was the mucus itself causing hypoxia/lung impairment or whether it was a different downstream effect of AhR. The AhR blockage also only partially ameliorated the effects of interferon exposure for some of the lung impairment measurements made (Fig 6B). So it's possible that it's another downstream effect interferon that causes the lung issues/hypoxia besides this AhR-mucus mechanism.



[Edit: they also should have shown all the lung capacity measurements after SARS-CoV-2 infection as comparison to see what proportion of its effect on the pulmonary system could be explained by interferon alone]

 

[Utsikt]

Interesting! A few random thoughts:

Would mucus induce coughing upon physical exertion?

And how long time does it take for the mucus to clear out?

Could mucus be detected through listening to the lungs with a stethoscope?